Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 26, Issue 2, Pages 443-456Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2007.02.002
Keywords
neuraminidase inhibitors; docking; scoring; protein-aligned CoMFA; multiple binding modes
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In this project, several docking conditions, scoring functions and corresponding protein-aligned molecular field analysis (CoMFA) models were evaluated for a diverse set of neuraminidase (NA) inhibitors. To this end, a group of inhibitors were docked into the active site of NA, The docked structures were utilized to construct a Corresponding protein-aligned CoMFA models by employing probe-based (H+, OH, CH3) energy grids and genetic partial least squares (G/PLS) statistical analysis. A total of 16 different docking configurations were evaluated, of which some succeeded in producing self-consistent and predictive CoMFA models. However, the best model coincided with docking the ionized ligands into the hydrated form of the binding site via PLP1 scoring function (r(LOO)(2) = 0.735, r(PRESS)(2) against 24 test compounds = 0.828). The highest-ranking CoMFA models were employed to probe NA-ligand interactions. Further validation by comparison with a co-crystallized ligand-NA crystallographic structure was performed. This combination of docking/scoring/CoMFA modeling provided interesting insights into the binding of different NA inhibitors. (c) 2007 Elsevier Inc. All rights reserved.
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